The Role of miR-125b in Cardiac Endothelial-to-Mesenchymal Transition and Cardiac Fibrosis

Cardiac fibrosis is the pathological hallmark of various end-stage cardiovascular disorders. It is caused by abnormal accumulation of fibroblasts in the myocardium, resulting in excessive deposition of extracellular matrix (ECM), and eventual heart dysfunction. Fibroblasts derived from endothelial cells by aberrant activation of endothelial-to-mesenchymal transition (EndMT) significantly contribute to fibrogenesis of the heart. In addition, induction of transforming growth factor-beta (TGF-beta) in response to cardiovascular injury plays a pivotal role in the activation of EndMT and fibrogenesis. However, the molecular basis of TGF-beta-induced EndMT in cardiac fibrosis is poorly characterized. In this study, we propose a novel antagomir approach to attenuate cardiac fibrosis by blocking EndMT. MicroRNAs (miRNAs) play a crucial role in pathogenesis of various cardiovascular diseases and have emerged as intriguing therapeutic targets. However, little is known about the role of miRNAs in the activation of EndMT or EndMT-induced cardiac fibrosis. Our recent findings indicate that specific miRNAs including miR-125b are significantly upregulated during TGF-beta-induced cardiac EndMT. Interestingly, miR-125b is reported to be upregulated in mice mid-embryogensis, during which EndMT is also activated. Importantly, we have observed significant upregulation of miR-125b in fibrotic human hearts as compared to healthy controls. In addition, miR-125b is also associated with other cardiovascular diseases, including cardiac hypertrophy, which may lead to cardiac fibrosis. Furthermore, we have observed that miR-125b is significantly upregulated in murine model of cardiac fibrosis. Importantly, our preliminary data shows that miR-125b plays an important role in EndMT. Based on these observations, we hypothesize that miR-125b potentiates cardiac fibrosis via TGF-beta-induced cardiac EndMT. The overall objective of this study is to elucidate the role of miRNAs in EndMT-induced cardiac fibrosis. Our long-term goal is to develop miR-125b as a novel molecular target against cardiac fibrosis. AIM 1: To identify the role of miR-125b in cardiac endothelial-to-mesenchymal transition in vitro. AIM 2: To investigate if specific miRNAs upregulated during cardiac EndMT are necessary for the induction of cardiac fibrosis in vivo.